JPH0532367B2 - - Google Patents

Abstract

A pharmaceutical composition for prophylaxis or treatment of ketosis in livestock which contains a dithia derivative represented by the general formula (I),wherein R and R' may be the same or different and are each indivisually a lower alkyl group, n is an integer of 0, 1 or 2; and A is a group of the formula, -CH_z-,(where M is a hydrogen atom or a salt-forming residue), -CH=CH-, -CH₂CH₂-,

Description

[Detailed description of the invention]

The present invention is based on the general formula () [R, R'; lower alkyl group n which may be the same or different; integer A of 0, 1, 2; -CH ₂ -,

[Formula] (M is H, salt-forming residue), -CH=CH-, -CH ₂ -CH ₂ -,

【formula】

The present invention relates to a therapeutic agent for ketosis in livestock containing a dithia derivative compound represented by the following formula. Until now, some of the compounds represented by the general formula () have already been published in Japanese Patent Publication Nos. 56-8576-9 as therapeutic agents for liver diseases in humans and animals, and as agricultural and horticultural fungicides in Japanese Patent Publication No. 51-34883 and Japanese Patent Publication No. 34883. No. 44-44526. The pharmacological action of some of the compounds represented by this general formula () as therapeutic agents for liver diseases is that liver function is affected by alcohol, malnutrition, viruses, drugs, poisons, etc.
The disease is caused by various factors such as bile duct obstruction and disorders of the hepatic circulation system, resulting in fatty liver, drug-induced liver disease, alcoholic hepatitis, viral hepatitis, depressed liver, liver damage due to cholestasis, jaundice, etc. When diseases such as liver cirrhosis arising from the etiology of liver disease appear, this compound exhibits (1) an action to promote liver protein synthesis, and (2) an action to suppress liver fibrosis, thereby restoring liver function and regenerating and activating hepatocytes. That is, it has been known to have the effect of acting on damaged liver to reduce and eliminate the damage. On the other hand, ketosis affects livestock, especially cows, and affected dairy cows suffer from poor appetite and weight loss.
It is characterized by symptoms of decreased milk production and deterioration of milk quality. Although the number of affected animals has reached a considerable number, the cause and mechanism of the disease are unknown, and no reliable treatment method has been established at present. Regarding the occurrence of ketosis up to now, the following points are explained in the special lecture on veterinary pathology written by Yamagiwa. In other words, the pathogenesis of ketosis has not been completely elucidated. First, as a development analysis, the first one is about digestion within the rumen. In the rumen, hydrous carbon is digested by the enzymatic activity of numerous microorganisms. At this time, volatile fatty acids (acetic,
butyrie and prepionie acida) are produced, and
It is absorbed and becomes an energy source for cows. Among these, acetic and butyric aeids produce ketone bodies, and propionic acid is counteractive to ketone body formation and is used for hepatic glycogen production. In terms of quantity, the former two account for 80% and the latter 20%. At the end of pregnancy, the normal balance is disrupted as the mother cow stores glycogen in her fetal liver and also transfers it to the milk during birth. When lactation begins, milk production suddenly increases from nothing, so nutrients are needed to make this much milk, and we must rely on enhanced digestion within the rumen. In dairy cows during lactation, hydrocarbon metabolism can only be carried out smoothly when there is a balance between nutritional intake and demand. Therefore, during childbirth at the end of pregnancy and during early lactation, health can only be maintained if the above processes are properly carried out. This means that nutritional requirements increase significantly during these times. However, during this period, women are forced to limit themselves in order to prevent breast engorgement. As delivery approaches, blood sugar levels continue to fall, and after delivery there is a sharp drop that continues for a period of time (hypoglycemia). During this period, ketone bodies are present in the blood. Ketone bodies are present in the blood of normal animals, but in trace amounts, at least 5 to 6 mg per cent, and in urine, at traces to 15 to 16 mg per cent, and do not show ketosis symptoms. Clinical ketosis is rarely seen when the cow's diet remains unchanged and the diet is adequate. If not, ketone bodies are deposited in the blood (80 mg per cent) and excreted in the urine (550 mg per cent). At the same time, blood sugar levels drop to 50% (20-30 mg per cent). i.e. ketonemia, ketonuria and
Once hypoglycemia is complete, clinical ketosis develops. As described in this article, ketosis is caused by a change in the eating habits of dairy cows and a loss of smooth hydrocarbon metabolism, resulting in acetic and butyric acid in the lower fatty acids mentioned above.
This is a symptom in which ketone bodies accumulate in the blood and are excreted in the urine, resulting in an acetone odor in the exhaled air and excreted urine. Due to these facts, in general, research is being done on husbandry management issues such as pre- and postnatal feed preparation for preventive purposes, but on the other hand, treatment methods have traditionally been (1) improving the nutrition and digestive function within the rumen; Promotion () Administration of digestive aids () Nutritional supplementation (glucose, sodium probionate, etc.) (2) Promotion of functions related to hydrated carbon metabolism in dairy cows For example, vitamins such as _B12 , liver tonics such as methionine, hormones, etc. Although research has been carried out on the administration of phthalate as a therapeutic measure, no significant medicinal effects have been expected. Based on such treatment cases, the present invention was conducted while conducting various studies on nutritional physiology, medical conditions, medications, etc. of mother cows, and found that a compound represented by the general formula () improves the abnormal accumulation of ketone bodies that occurs during ketosis. death,
They discovered that it has a remarkable effect on relieving ketosis. In the definition of A in this general formula (), the salt-forming residue of M specifically represents, for example, a sodium atom, a potassium atom, an ammonium group, an organic amine, etc. Representative examples of the compounds represented by the above general formula () and their toxicity are shown in the following table.

[Table] When administering these medicinal ingredients of the present invention to sick animals, the medicinal ingredients may be administered alone or in the form of formulations commonly used in pharmaceuticals, such as powders, granules, etc.
The drug is administered in the form of tablets, sugar-coated tablets, capsules, suspensions, ampoules, injections, etc., in the appropriate amount. The dosage of the veterinary drug of the present invention depends on the type of livestock, age,
Although it varies depending on body weight, season, medical condition, etc., in the case of oral administration, 0.1 to 250 mg, preferably 1 to 100 mg, per 1 kg of body weight per day, and in the case of parenteral administration,
A range of 0.01 to 250 mg is advantageous. The test method is shown below. The active ingredient of the present invention was made into a granule as shown in Example 1, and the prescribed dosage was forcibly orally administered to dairy cows suffering from ketosis once a day for 6 weeks. Before administration and 1 week, 3 weeks, and 6 days after administration
A week later, various measurements were taken in blood and urine. Serum biochemical tests were performed using serum obtained by centrifuging collected blood after coagulation (3000 rpm, 15 mm). Blood glucose levels were measured using the glycose oxidase method, free fatty acids were measured using the ACS-ACO-POD method, and blood ketone bodies were measured using the ACS-ACO-POD method. Quantification was performed using a diffusion colorimetric method (THIN-ROBERTSON method) using Salieyl aldehyde. Urinary ketone bodies were determined using Lovestatx (Milesu Sankyo). As shown in the table below, the high concentration of acetoacetic acid in the blood, which is characteristic of ketosis before dosing, was improved by the administration of the compound according to the invention, and after 3 to 6 weeks of administration. returned to normal values. In addition, free fatty acids, which are used to treat ketosis, showed normal values 3 to 6 weeks after administration. In a test for ketone bodies in the urine, almost no ketone bodies were detected 3 weeks after administration. As for the general symptoms, the patient's appetite for eating gradually recovered after administration, and returned to normal after 3 weeks. Milk production also returned to normal within 3 to 4 weeks of administration. From these results, it is clear that the compounds of the present invention are extremely effective against ketosis dairy cows.

[Table] ...Detectable - ...Not detectable Example 1 Compound No. 6 50 parts, light anhydrous silicic acid 15.0 parts, precipitated carbon 5.0 parts, cornstarch 5.0 parts, crystalline cellulose 20.0, polyvinyl alcohol 5 parts, water 30
After uniformly mixing and kneading the mixture, the mixture is crushed, granulated, dried and sieved to form granules, which are then forcibly administered orally as described above for use in the treatment of ketosis in dairy cows. Example 2 30 parts of compound No. 4 and 70 parts of common salt were mixed uniformly,
This is compression molded, used as a fixative, and licked to prevent or treat ketosis in dairy cows. Example 3 Compound 6 30 parts, magnesium propionate 30
part, 30 parts of calcium carbonate, tertiary calcium phosphate
Mix 10 parts and make a powder. This is used alone for the treatment of ketosis in cattle etc. Furthermore, for forced oral administration of powders and the like, an appropriate amount of water, milk, etc. is used. Similarly, it has been found that when the compounds of the present invention are used in combination with energy sources such as glycose and propionic acid, the above-mentioned therapeutic effects are further enhanced. Example 4 0.5 parts of Compound 4, 2.5 parts of nonionic surfactant, and 97 parts of physiological saline are mixed and sterilized under heating to prepare an injection.

Claims (1)

[Claims] 1 General formula () [R, R'; lower alkyl group n which may be the same or different; integer A of 0, 1, 2; -CH ₂ -, [Formula] (M is H or a salt-forming residue), -CH=CH- , -CH ₂ -CH ₂ -, [Formula] [Formula]] A therapeutic agent for ketosis in domestic animals, which contains a dithia compound represented by the following formula. 2 In claim 1, the compound represented by the general formula () in claim 1 is diisopropyl 1,3-dithiolan-2-ylidenemalonate or diisopropyl 1,3-dithiol-2-ylidenemalonate. The therapeutic agent described. 3. Add dithia compound at 0.1 per kg of animal body weight per day.
Granules, tablets, etc. so that they can be orally administered alone to sick animals in the range of ~250mg, preferably 1~100mg.
The therapeutic agent according to claim 1, which is in the form of a sugar-coated tablet, capsule, or the like. 4. Add dithia compound at 0.01 per kg of animal body weight per day.
Claim 1 in the form of ampoules and injections for parenteral administration in the range of ~250mg
Therapeutic agents described in Section.